Imaging system and methods of high resolution cherenkov dose images

ABSTRACT

A Cherenkov imaging system includes a high-speed radiation detector configured to provide a first timing signal synchronized with pulses of radiation to control operation of at least one pulse-gated, multiple-pulse-integrating, (PG-MPI) CMOS camera synchronized through the digital time signal to pulses of the radiation beam source, to image Cherenkov radiation; and a digital image-processing system. The high-speed radiation detector is either a solid-state radiation detector or a scintillator with a photodetector. The system images Cherenkov light emitted by tissue by using a timing signal synchronized to pulses of a pulsed radiation beam to control the PG-MPI camera by integrating light received by the PG-MPI camera during multiple pulses of the radiation beam while excluding light received by the camera between pulses of the radiation beam.

PRIORITY CLAIM

The present application claims priority to U.S. Provisional PatentApplication No. 62/967,302 filed 29 Jan. 2020. The entire contents ofthe aforementioned provisional application are hereby incorporatedherein by reference.

GOVERNMENT SUPPORT

This invention was made with government support under grant numbers R01EB023909 and grant subcontract (Doseoptics LLC) R44 CA232879 awarded byNational Institutes of Health. The government has certain rights in theinvention.

BACKGROUND

High-energy particle or photon beams are used in treatment of manycancers. Such beams are typically provided by a linear accelerator(LINAC), or related apparatus. When treating cancers with radiation itis desirable to target the beam in time and space such that there is ahigh net ratio of energy deposited in the tumor relative to energydeposited in normal tissues outside the tumor, resulting in a hightherapeutic ratio of tumor to normal tissue dose.

When treating patients with a high-energy radiation beam it is desirableto verify that the beam shape is as planned. Additionally, when beamsenter tissue it is important to accurately predict how radiation beamshape varies with depth in tissue, to ensure adequate dosage to tumortissue while minimizing dosage to surrounding normal tissues. If beamshape and orientation are adjusted, such as by positioning deflectionmagnets or shielding devices, it is important to confirm the resultingbeam shape and dosage profile are as desired. Radiation treatmentcenters may therefore desire to confirm beam shape and dose profile foreach patient or as part of routine calibration and maintenance.Moreover, aiming, shaping, timing, and other characteristics oftherapeutic radiation beams should be verified during routine qualityassurance or quality audit and recalibration prior to the administrationof treatment to patients, where inadvertent exposure of non-tumor tissueto radiation must be minimized.

In fact, manufacturers of radiation treatment devices routinely documentbeam shapes and dosage profiles produced by common configurations oftheir devices for training and guiding operators in using theirmachines. Further, they must seek regulatory approvals of theirmachines, and, as part of the regulatory approvals process, must providedocumentation of beam shapes and dosage profiles achievable by theirmachines. Manufacturers therefore also need to accurately verify anddocument beam profiles for this regulatory approval process.

Cherenkov light emitted by tissue, or by media with radiologicalproperties similar to those of tissue (such as water), can be used as aproxy for radiation delivered to tissue and to other media. Cherenkovlight has been used for qualitative applications, in systems that detectCherenkov radiation emitted by tissue and other media in real-worldclinical settings, however, these systems required direct interfacing tothe LINAC.

Current Cherenkov imaging camera systems require interfacing with LINACtiming signals to support Cherenkov imaging synchronized to during beampulses and background imaging with beam off. Such synchronized operationwith the LINAC allows imaging optically weak Cherenkov light emissionsin well-lit rooms. Although these synchronization signals are accessiblethrough standard LINAC service panels, electrical interfaces must becarefully designed to make sure there is no interference with normalLINAC operations. Access to these signals requires rigorous verificationand validation requirements on interfacing electronics, as well asapprovals from LINAC vendors and regulatory authorities.

As mentioned above, Cherenkov light emissions from a medical LINAC'sbeam in water or tissue are weak and appear in brief pulses. Thesepulses are short enough, and the Cherenkov emissions weak enough, thattypical CMOS image sensors fail to provide adequate images. An imagingtechnology that has successfully imaged Cherenkov light is animage-intensified, gated, electronic camera with a gated imageintensifier tube positioned to intensify light received from the tissue,and an electronic camera positioned to record images from the imageintensifier tube.

SUMMARY

The present system is a Cherenkov-based imaging system that may use aremote, beam sensing, radio-optical triggering unit (RTU) which does notrequire an electrical interface to a LINAC. The RTU provides triggersignals for Cherenkov and background imaging. The radio-opticaltriggering unit, as well as related systems and methods, leveragesscattered radiation present in the room during radiation treatment withhigh-speed, highly sensitive radio-optical sensing to generate a digitaltiming signal synchronous with the treatment beam for use in triggeringCherenkov radiation cameras.

The system and method provides for rapid and economic characterizationof complex radiation treatment plans prior to patient exposure,utilizing a radio-optical triggering unit (RTU). Further, the system andmethod provide for economically imaging Cherenkov radiation emitted bytissue and other media in real-world clinical settings, such as settingsilluminated by visible light, utilizing the RTU.

The present system is also directed to Cherenkov-based imaging systemsthat use a pulse-gated, multiple-pulse-integrating, (PG-MPI) CMOS imagesensor array synchronized to radiation pulses provided by the LINACusing either the remote, beam-sensing, (RTU) triggering solution fortiming or a direct electrical interface to the LINAC for timing.

In an embodiment, a Cherenkov imaging system includes a high-speedradiation detector configured to provide a first timing signalsynchronized with pulses of radiation provided by a pulsed radiationbeam source; the timing signal coupled to control operation of at leastone camera capable of imaging Cherenkov radiation; and a digitalimage-processing system; where the high-speed radiation detector isselected from the group consisting of solid-state radiation detectorsand radiation detectors of the type comprising a scintillator and aphotodetector; and where the at least one camera capable of imagingCherenkov radiation is a pulse-gated, multiple-pulse-integrating,(PG-MPI) camera synchronized through the digital time signal to pulsesof the radiation beam source.

An imaging unit has a trigger input adapted for connection to a beam-onoutput signal provided by a pulsed radiation beam source, the triggerinput receiving a digital timing signal; apparatus configured tocommunicate the digital timing signal to trigger operation of at leastone camera capable of imaging Cherenkov radiation; where the cameracapable of imaging Cherenkov radiation is a pulse-gated,multiple-pulse-integrating, (PG-MPI) camera synchronized through thedigital time signal to pulses of the radiation beam source.

In another embodiment, a method of imaging Cherenkov light emitted by aphantom or tissue includes providing a timing signal synchronized topulses of a pulsed radiation beam; applying the pulsed radiation beam tothe phantom or tissue, the pulsed radiation beam causing the phantom ortissue to emit the Cherenkov light; imaging the Cherenkov light with apulse-gated, multiple-pulse-integrating, (PG-MPI) camera; imaging theCherenkov light being performed by integrating light received by thePG-MPI camera during multiple pulses of the radiation beam and notintegrating light received by the PG-MPI camera between pulses of theradiation beam.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, like reference characters generally refer to the sameparts throughout the different views. The drawings are not to scale,emphasis instead being placed upon illustrating principles of the systemand method.

FIG. 1A schematically depicts an illustrative system for performingmonitored radiotherapy with time-controlled room lighting and camerasensing of light emissions from a subject.

FIG. 1B is a diagram showing the approximate relationships of roomlighting, beam pulses, light emissions, and camera shutter windows inthe system of FIG. 1A.

FIG. 2 is a schematic block diagram of an apparatus for coordinateddirect feedback observation and adjustment/control of high-energy beamprofiles in a therapeutic radiation system while imaging the beamdepositing dose in a phantom.

FIG. 3 is a flow chart of an illustrative method of operation of thesystem of FIG. 2 .

FIG. 4A is a schematic block diagram of an apparatus for the calibrationof Cherenkov observations to in situ, high-accuracy radiationmeasurements in a therapeutic radiation system and phantom.

FIG. 4B is a more detailed view of portions of the system of FIG. 4A.

FIG. 5 is a schematic block diagram of an apparatus for coordinatedCherenkov and non-Cherenkov observation of high-energy beam profiles ina therapeutic radiation system.

FIG. 6A shows a schematic of one embodiment of a radio-opticaltriggering unit, which comprises a high speed, highly sensitiveradio-optical sensing system to generate a digital timing signal whichis synchronous with the treatment beam.

FIG. 6B is a schematic of two radio-optical triggering units withoutputs AND-ed to suppress spurious triggers.

FIG. 7A is a schematic depicting one embodiment where the RTU placedwithin a central interface box, which distributes the synchronizationsignal to multiple connected cameras along with power.

FIG. 7B is a schematic depicting one embodiment where the RTU is housedwithin a camera enclosure.

FIG. 8 is a representation of the case and components certainembodiments of the RTU.

FIG. 9 is a graph that depicts an optical trigger signal matching bothTARG-I and KLY-V signals.

FIG. 10A provides multiple Cherenkov images indicating opticaltriggering matching TARG-I triggering.

FIG. 10B provides multiple Cherenkov images and data indicating opticaltriggering matches the TARG-I triggering in location and intensity.

FIG. 11 is a block diagram of a versatile RTU providing raw pulsesindicative of detected radiation pulses, synthesized pulses synchronizedto detected radiation pulses, synthesized pulses immediately followingdetected radiation when fluorescent emissions are expected, andsynthesized pulses leading expected radiation pulses for backgroundimage capture.

FIG. 12 is a timing diagram of the versatile RTU of FIG. 11 .

FIG. 13 is a flowchart of operation of the versatile RTU of FIG. 11 .

FIG. 14 is a timing diagram of an enhanced RTU.

FIG. 15 is an exemplary schematic diagram of a photosensor cell of apulse-gated, multiple-pulse-integrating, photodiode detector.

FIG. 16 is an exemplary timing diagram of operating a pulse-gatedphotodiode detector to integrate received Cherenkov light generated overmultiple pulses of a particle-accelerator beam.

FIG. 17 is an exemplary composite photograph of Cherenkov radiation andbackground image captured sequentially with a gated,multiple-pulse-integrating, CMOS image sensor.

FIG. 18A is an exemplary single-frame photograph of Cherenkov radiationcorrected by subtracting an integrated background.

FIG. 18B is an exemplary photograph of Cherenkov radiation captured witha gated, multiple-pulse-integrating, CMOS image sensor over 200 framescorrected by subtracting background, showing significant improvement inimage quality over the single-frame photograph of FIG. 18A.

FIG. 19 is an exemplary integrated background image captured over 200beam pulses.

FIG. 20 is an exemplary flowchart of a method of using a pulse-gated,multiple-pulse-integrating, camera with background subtraction to imageCherenkov radiation.

DETAILED DESCRIPTION

Embodiments of the present system are directed to Cherenkov-basedimaging systems for high resolution radiation dose images using aremote, beam sensing triggering solution which does not require anelectrical interface to a pulsed radiation beam source for timing. Inembodiments, the pulsed radiation beam source may be a linearaccelerator (LINAC), cyclotron, synchrotron, or similar device.

Embodiments of the present system are directed to Cherenkov-basedimaging systems that use a gated, multiple-pulse-integrating, CMOS imagesensor array with either the remote, beam-sensing, triggering solutionor a direct electrical interface to a LINAC for timing.

Charged particles (e.g., electrons, positrons, protons, alpha particles)moving faster than the speed of light in a dielectric medium deceleratewhile emitting photons. These photons are termed Cherenkov (a.k.a.“Cerenkov” and similar spellings) radiation. In particular, chargedparticles moving with sufficient speed cause Cherenkov radiationemission in human tissue or water. Cherenkov radiation can also resultfrom irradiation by high-energy photons used in cancer therapy (e.g.,6-18 MV), because Compton scatter of these photons produce secondaryelectron emission having sufficient kinetic energy to produce Cherenkovradiation in the medium. Cherenkov emission in human tissue has beendetected with incident radiation in the range of 6 to 24 MeV energiesfor electrons and x-ray photons. Although no particle of nonzero masscan move at or above the speed of light in vacuum (velocity c), it iscommon that particle velocities can exceed the speed of light v in amaterial media, v being less than c, when excited to kinetic energiesgreater than a few hundred kiloelectron volts (keV). Since Cherenkovemission depends on particle velocity, more-massive particles (e.g.,protons, alpha particles) need correspondingly higher energies toproduce Cherenkov radiation in a given medium, and so Cherenkov is onlyemitted from larger-mass charged particles such as protons atconsiderably higher kinetic energy than required for electrons.

Cherenkov radiation (or “Cherenkov light”) is emitted at an acute angleθ to the path of a particle moving at velocity v_(p), where cosθ=c/(nv_(p)) and n is the refractive index of the medium; when numerouscharged particles move at suitable velocity in a collimated beam, aCherenkov glow is emitted in a conic pattern at angle θ to the beam,which is approximately 41 degrees from the direction of travel.Cherenkov emission has a continuous spectrum across the entireultraviolet, visible, and near-infrared spectrum with intensity varyingas the inverse square of the wavelength (up to a cutoff frequency).Thus, Cherenkov emission at higher frequencies (shorter wavelengths) ismore intense, giving rise to Cherenkov light's characteristic blue colorwhen viewed by eye or camera.

When Cherenkov light is induced locally inside water or tissue, it ispredominantly blue in color, but with a broad spectrum which tapers offinto the green, red, and near-infrared (NIR) with an inverse squarewavelength dependence given by the Frank-Tamm formula. This light whenemitted within tissue is attenuated by absorbers significantly reducingthe blue green wavelengths and largely just leaving the red and NIRwavelengths for transmission over a few millimeters. This light in thetissue can also excite other molecular species within the tissue toinduce photo-luminescence (i.e., fluorescence or phosphorescence).

Cherenkov light is of significance for medical radiation systems becauseits intensity at any given point in a volume of tissue, as captured byimaging equipment, correlates with the intensity at that point ofradiation that meets the criteria for inducing Cherenkov light.Cherenkov light emission is thus a proxy for high-energy radiationintensity. Therefore, Cherenkov light enables quantitative and relativeobservation of a high-energy radiation beam by an imaging device (e.g.,camera) not aligned directly with the beam and thus not subject todamage by it.

Accordingly, we describe systems, tools, and methods for using Cherenkovlight emission from an intersection of a pulsed radiation beam from astandard linear accelerator, or other pulsed accelerator, with a subjector phantom, including emission of fluorescent light from fluorophoresstimulated by Cherenkov light, to localize and quantify the radiationbeam. In certain embodiments, operative feedback including Cherenkovimaging, e.g., of a phantom (nonliving test object), is employed toenable a human operator or computational system to adjust a therapeuticradiation machine or plan of treatment for purposes of design,commissioning, quality auditing, adjustment, treatment planverification, or the like in real-time.

In certain other embodiments, localized high-accuracy measurements oftherapeutic radiation flux by an additionally available measurementdevice such as an external portal imaging device, ionization chamber, ordiode, are integrated with Cherenkov imaging to produce Cherenkovvisualizations of dose delivery calibrated to accurate dose units. Insome embodiments, high resolution dose images are provided intomographic or otherwise enhanced characterizations of therapeuticradiation beam profiles.

The Cherenkov-based imaging systems, tools, and related methods aredescribed with reference to the following definitions that, forconvenience, are set forth below:

I. Definitions

As used herein, the term “a,” “an,” “the” and similar terms used hereinare to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

The term “camera” herein describes an electronic camera capable ofimaging Cherenkov radiation and/or radiation emitted by fluorescentsubstances (fluorophores) excited by Cherenkov radiation.

The term pulse-gated, multiple-pulse-integrating, (PG-MPI) camera hereindescribes a camera as described above with the ability to image lightreceived during a pulse of a timing signal, while ignoring lightreceived at times other than during pulses of the timing signal.Further, the PG-MPI camera can integrate light detected during multiplepulses of the repetitive timing signal to provide a stronger image thancan be achieved by imaging light only during a single pulse of thetiming signal. We have discovered that a commercial-grade time-domainTime-of-Flight (ToF) CMOS image sensor, the Teledyne e2v BORA®1.3-megapixel image sensor, can be configured as a PG-MPI image sensorin a way that is capable of detecting Cherenkov light from tissue. It isexpected that similar image sensors may become available with greaternumbers of pixels, and other technologies may be able to produce futurePG-MPI image sensors. A PG-MPI image sensor may be synchronized topulses of the radiation beam source to selectively capture images oflight either during pulses of the radiation beam while ignoring lightreceived between pulses of the radiation beam for Cherenkov images, oralternatively synchronized to capture images of light received between,but not during, pulses of the radiation beam source for backgroundimages.

The term “interface” is used herein to describe a shared boundary acrosswhich two separate components of a system exchange information, whichcan be between software, computer hardware, peripheral devices, humansand combinations of these. Moreover, the operation of two separatecomponents across the boundary, as in the interaction of the camerainterface which is designed to interface with the camera, is referred toherein as “interfacing.” In certain embodiments, the interfacing may bebi-directional. In other embodiments, the interfacing may beunidirectional. In specific embodiments, the term “interface” mayreference a user interface such as a graphic user display and keyboard.

The term “high-energy radiation” is used herein to describe radiationthat, considering the mass of particles involved, contains enough energyto generate Cherenkov radiation upon entry into a given medium with agiven refractive index. As such, the use of the language “high-energyradiation” herein considers both the delivered particle and the mediumirradiated.

The term “isocenter” herein references a point in space relative to thetreatment machine which indicates the center of the treatment volume,e.g., in a system where various components system rotate, the isocenteris the point about which the components rotate. Location of theisocenter plays an important role in treatment planning, since ideallythe isocenter should be centered in the target volume such as centeredin a tumor; thus, patient positioning with respect to the isocenter is asignificant factor for successful irradiation of cancerous tissue andconsequently for treatment outcome.

The language “machine-readable medium” describes a medium capable ofstoring data in a format readable by a machine. Examples ofmachine-readable media include magnetic media such as magnetic disks,cards, tapes, and drums, punched cards and paper tapes, optical disks,barcodes, magnetic ink characters, and solid-state devices such asflash-based thumbdrives, solid-state disks, etc. In a particularembodiment, the machine-readable medium is a network server disk or diskarray. In specific embodiments, the machine-readable medium occupiesmore than one network server disks.

The term “subject” as used herein is to describe the object beingirradiated with radiation, such as a phantom or human tissue.

The term “user” or “operator” are used interchangeably to describe anyperson that operates the systems of the present system by interfacingwith a user interface.

II. Advancements in Cherenkov-Based Imaging Systems

Cherenkov-based imaging systems offer instantaneous radiation surfaceimaging of a subject exposed with high-energy radiation, toqualitatively record and verify accuracy of treatment at the time ofexposure. Such systems generally include at least one camera capable ofimaging Cherenkov light, an image processor, and a machine-readablemedium designed to record and store the information; capture of theCherenkov light from the subject is typically triggered by a signaltapped directly from a pulsed radiation beam source such as a LINAC thatprovides pulsed radiation to the subject.

In contrast, the advanced Cherenkov-based imaging systems hereindescribed use a radio-optical triggering unit (RTU) instead of a signaltapped directly from a LINC and provide enhanced system features thatafford the systems to more actively use this information through (1)feedback presentation of this information to control the radiation beamsource; (2) quantification of dose based on Cherenkov imaging, providinghigh resolution images; and (3) improved dynamic range image capturethrough use of the beam sensing triggering solution described herein.

As such, one embodiment provides an advanced Cherenkov-based imagingsystem including:

-   -   a radiation beam source (e.g., a particle accelerator or other        device for providing high-energy radiation, which, for example,        may be cross-sectionally shaped by a beam-shaping apparatus,        e.g., a multi-leaf collimator);    -   at least one camera capable of imaging Cherenkov radiation        (and/or radiation emitted by fluorescent substances        (fluorophores) excited by Cherenkov radiation); and    -   one or more processing units that enables the control of the        radiation beam source,

wherein the Cherenkov radiation is detected by the camera after exposureof a subject to high-energy radiation from the radiation beam source. Incertain embodiments, systems have desirable properties such as rapidity,three- and four-dimensionality, and water equivalence.

In certain embodiments, the systems include an illumination systemadapted to substantially reduce interference with wavelengths ofinterest by using an LED illumination system.

FIG. 1A, FIG. 1B, and FIG. 2 , described further herein below, depictcertain aspects of systems that are relevant to various embodiments.

FIG. 1A schematically depicts portions of an illustrative external-beamradiation therapy system 100 like a system described in U.S. ProvisionalPatent Application No. 62/153,417. System 100 provides context relevantto various embodiments described herein. System 100 depictshigh-sensitivity electronic cameras or groups of cameras 102, 104 usedto image Cherenkov light and/or light emitted by fluorescent substances(fluorophores) excited by Cherenkov light and to localize locations onor in a human subject 106 from where this light is emitted. In certainembodiments, the subject 106 is preferably located within an environmentfrom which light from uncontrolled sources, such as the sun andincandescent lamps, is excluded or minimized. In certain embodiments ofthe system 100 depicted in FIG. 1A, the subject 106 is placed in thepath of a radiation beam 108 so that the beam 108 irradiates tissue 110of the subject in need of radiation treatment, such as a tumor. Beam 108is provided by a radiation beam source 112, e.g., a particle acceleratoror other device for providing high-energy radiation, and typically iscross-sectionally shaped by a beam-shaping apparatus 114, e.g., amulti-leaf collimator.

In the illustrative system 100 of FIG. 1A, the source 112 is anaccelerator that provides a beam 108 of electrons having energy ofbetween 6 million electron volts (6 MeV) and 24 MeV, such as is used todeliver treatment energy to deep tumors as opposed to treatment ofsurface skin. Various other therapeutic systems could produce, forexample, a photon beam of 6 MeV or higher or a high-energy proton beam.In general, various embodiments are combined with therapeutic radiationsystems that produce beams capable of inducing Cherenkov radiationemission in human tissue, including but not limited to systems describedexplicitly herein.

In certain embodiments like system 100, cameras 102, 104 image thesubject 106 from fewer or more points of view than are depicted in FIG.1A, or non-stereoscopic cameras are used, or a single camera is arrangedto move to more than one position with respect to the subject, or thesubject 106 is supported in a manner that permits their rotation withrespect to one or more cameras, or some combination of one or more ofthese or other imaging arrangements is employed. Cherenkov and/orfluorescent radiation emission occurs where the tissues (or tissueequivalent) of the subject 106 are irradiated by the beam 108, a volumeherein termed the emission volume 116. Fluorescent light emissions canbe induced by Cherenkov-light excitation of fluorophores in tissue,where such fluorophores are present, and are radiated isotropicallyrather than directionally as is the case with Cherenkov radiation.

In certain embodiments, the cameras 102, 104 are aimed to image at leastpart of the emission volume 116 and are coupled to a camera interface118 of an image-processing system 120. Camera connections to the camerainterface 118 may be wired or wireless and are not depicted in FIG. 1Afor clarity. Herein, in certain embodiments, camera connections mayserve both to transfer image data from a camera to the camera interface118 and to convey commands (e.g., for setting shutter timing, exposure)from the camera interface 118 to the camera. In certain embodiments likesystem 100, light-modifying components such as filters and lightintensifiers are aligned with cameras, or included in cameras, tointensify and/or selectively admit Cherenkov and/or fluorescence light;however, such light-modifying devices are omitted from FIG. 1A forsimplicity. The camera interface 118 captures and stores digital imagesfrom the cameras 102, 104 in memory 122 for later retrieval andprocessing by at least one processor 124 of the image processing system120. The processor 124 can exchange information not only with the camerainterface 118 and memory 122 but with a timing interface 126, a displaysubsystem 128, and potentially other devices as well. The displaysubsystem 128 communicates with a user interface 130 through which auser 132 can interact with the imaging-processing system 120. In certainembodiments, timing interface 126 is adapted to communicate with asystem interface 134 of the radiation therapy device 136 to determinetiming of pulses of radiation from the beam source 112 and to controlpulsed room lighting 138 to mitigate interference from room lightingduring imaging of Cherenkov emissions and/or fluorescence bysynchronizing lighting with image capture by cameras 102, 104, asdiscussed below with reference to FIG. 1B.

In certain embodiments of the system 100 of FIG. 1A, the imaging systemcameras 102, 104 are spectrally-sensitive cameras capable of providingspectral data permitting distinction between Cherenkov and fluorescentlight. Emitted Cherenkov and fluorescent light is subject to attenuationby absorbance as it propagates through and emitted by tissue, and insome embodiments spectrally-sensitive cameras permit distinction betweenlight absorbed by oxyhemoglobin and by deoxyhemoglobin.

In certain embodiments of the systems, for example in the system 100 ofFIG. 1A, raw or de-noised images from the imaging system are recorded inone or more suitable digital memory systems (e.g., memory 122) asdocumentation of the radiation treatment.

In certain embodiments, prior to each session for which monitoring ofradiation delivery is desired, an enhancing and indicating agent isadministered to the patient. In a particular example, the enhancing andindicating agent is a dose in the range of 20 milligrams per kilogrambody weight of 5-delta-aminolevulinic acid (5-ALA), administered for anincubation time of approximately four hours before each dividedradiotherapy session begins. In specific embodiments with ametabolically active tumor in tissue 110 of the subject, some of the5-ALA is metabolized to protoporphyrin IX (PpIX), which fluoresces whenilluminated by Cherenkov light. PpIX production in normal tissue andmetabolically active tissues 110 is generally understood to beproportional to metabolic processes in those tissues; thus, ametabolically active tumor will tend to contain more PpIX and fluorescemore brightly. Other enhancing agents may be developed or utilized withthe system described herein.

The system and method provide simple, accurate, quick, robust,real-time, water-equivalent characterization of beams from LINACs andother systems producing external-therapy radiation utilizing aradio-optical triggering unit (RTU) for purposes including optimization,commissioning, routine quality auditing, R&D, and manufacture.

The radio-optical triggering unit, as well as related systems andmethods, leverages the scattered radiation present in the room duringthe treatment and employs high-speed, highly sensitive radio-opticalsensing to generate a digital timing signal which is synchronous withthe treatment beam for use in triggering Cherenkov radiation detectionand does not rely on any electrical signal from the LINAC itself.

A. Radio-Optical Triggering Unit (RTU)

As such, one embodiment provides a radio-optical triggering unit (RTU)that performs a method including steps of:

-   -   detection of scattered radiation by a fast response time        scintillator (SCI) coupled with a high speed, single-photon        sensitive silicon photomultiplier module (SiPM) to detect        exposure of a subject to high-energy radiation from a radiation        beam source;    -   the SCI performs conversion and amplification of the scattered        radiation into optical photons, while the SiPM generates an        analog electrical signal;    -   processing the analog signal to a digital timing signal, e.g., a        transistor-transistor logic signal, wherein the digital timing        signal is synchronized with the radiation beam source; and    -   communication of the digital timing signal to trigger the        operation of at least one camera capable of imaging one or more        signals, e.g., Cherenkov radiation or scintillation signals        (e.g., from scintillation patches placed on the patient's body).

In an alternative embodiment, the RTU times pulses of the high-energyradiation to provide a timing signal of improved accuracy, to provideinterpolated signals early in each interval between beam pulses whenfluorescent emission is present, and to provide interpolated signalslate in each interval between beam pulses when only backgroundillumination is present.

In one embodiment, the timing signal generated by the RTU may be used toperform synchronous imaging of Cherenkov radiation produced by thetreatment beams in tissue or other synthetic materials, as detailedherein. In an alternative embodiment, the timing signal generated by theRTU is used to perform synchronous imaging of scintillation signalsproduced by the treatment beams in tissue or other synthetic materialsin the same manner as imaging the Cherenkov signals.

FIG. 6A shows a schematic of one embodiment of a radio-opticaltriggering unit, including a high speed, highly sensitive radio-opticalsensing system to generate a digital timing signal synchronous with thetreatment beam. For example, the RTU converts and amplifies scatteredionizing radiation into optical photons, which is detected by a fastresponse time scintillator coupled with a high speed, single photonsensitive silicon photomultiplier module (SiPM), and the analogelectrical signal generated by the SiPM is conditioned and converted toa digital (transistor-transistor logic) TTL signal by the signalprocessing unit (SPU).

In certain embodiments of the radio-optical triggering unit (RTU), thetime signal is synchronized with the radiation beam source to triggerthe operation of at least one camera capable of imaging Cherenkovradiation to detect Cherenkov radiation during beam pulses and imagingbackground images at times when beam pulses are not present. Inparticular embodiments, such synchronized operation with the LINACallows imaging optically weak Cherenkov light emissions in well-litrooms.

In certain embodiments of the radio-optical triggering unit (RTU), thestep of communication is capable of instructing modification ofadditional downstream electronics and imaging system functions.

In certain embodiments of the radio-optical triggering unit (RTU), therising edge of the timing signal is synchronous with the radiation beamsource and is used to trigger the operation of at least one cameracapable of imaging Cherenkov radiation. In certain embodiments, therising edge of the timing signal is used for gating additionaldownstream electronics and imaging systems, e.g., such as the camera,e.g., C-Dose™ camera.

In certain embodiments of the radio-optical triggering unit (RTU), thefast response scintillator SCI is encapsulated in a light tightenclosure.

In certain embodiments, the signal from RTU fully substitutes for theLINAC supplied sync signals, such as TARG-I (typically used for imagingphoton beams) or KLY-V (typically used for imaging electrons), which aretypically used to synchronize the operation of prior cameras for imagingCherenkov radiation with LINAC operation. In this respect, FIG. 9depicts the optical trigger signals matching both TARG-I and KLY-Vsignals. Furthermore, FIG. 10A shows optical triggering matching theTARG-I triggering visually and 10B shows the optical triggering matchesthe TARG-I triggering in location and intensity.

In certain embodiments with the RTU, the system further comprises acommunication tool with one or more processing units that enables thecontrol of a radiation beam source.

In certain embodiments of the system, the system includes a radiationbeam source. In certain embodiments, the radiation beam source is aparticle accelerator, LINAC, or other device for providing high-energyradiation. In particular embodiments, the radiation beam source may becross-sectionally shaped by a beam-shaping apparatus. In specificembodiments, the beam-shaping apparatus is a multi-leaf collimator.

In certain embodiments of the advanced triggering systems, the systemfurther comprises one or more additional radio-optical triggering units,multiple RTU modules being used to implement a co-incidence triggeringmechanism. This design allows rejection of possible spurious triggeringof the SCI, and coupled SiPM due to spontaneous emissions from thescintillator crystal or cosmic ray interactions. FIG. 6B below shows aschematic of this implementation employing two RTUs, where each of thesemodules are shown to be sensing a spurious trigger during the normaloperational mode. In particular embodiments the outputs from two RTUmodules are combined using a logical AND gate. Since spurious triggersoccur randomly in time the AND gate effectively suppresses them at theoutput; but the radiation beam is sensed by both the RTUs and validtriggers synchronous with each other are passed to the cameras. Incertain additional embodiments, the two RTUs are spatially separated, toreduce potential for spurious triggers.

The RTUs may be compact and independent sensing modules, and as such,they may be configured in many ways to improve redundancy, and supportself-contained operation of Cherenkov imaging camera systems.Accordingly, and without intending to limit the system architectureincluding an RTU a system may include multiple RTUs, each RTU may beencompassed within camera units or may be separate from the camera. FIG.7A shows one configuration where the RTU module is placed within acentral interface box, which distributes the synchronization signal tomultiple connected cameras along with the power. The RTU module in thisdepiction may be a basic unit or a coincidence triggering variant, whichoffers additional redundancy in the case of one of the RTU unitsfailing. In an alternative embodiment, as shown in FIG. 7B, an RTU ishoused within each camera enclosure. This configuration offers cameralevel redundancy and enables simple single camera designs with built-intriggering capabilities.

In certain embodiments of the advanced triggering systems, the systemfurther comprises an integrated power supply unit (PSU), e.g., thatprovides power to the radio-optical triggering unit, e.g., SCI and,e.g., coupled SiPM.

B. Direct Feedback Interface Control Units and Systems

In certain advanced Cherenkov-based imaging systems utilizing aradio-optical triggering unit (RTU), the system further provides directfeedback of the image information derived from capturing real-timeCherenkov radiation administration to instruct on the control of thebeam source and/or beam shape. In certain embodiments, this isaccomplished by means of incorporation of a direct feedback interface(DFI) control unit, wherein the DFI control unit is designed to providedirect/real-time communication between the camera and the radiation beamsource unit and/or beam shaping unit (e.g., collimator), e.g., via auser display. Moreover, the Cherenkov-based feedback to the radiationbeam source and/or beam shaping unit, may be used by developers orservice people to optimize the radiation beam source and/or beam shapingunit.

As such, another embodiment provides a direct feedback interface (DFI)control unit including a processor configured by firmware to perform amethod comprising:

-   -   detection of Cherenkov radiation (and/or radiation emitted by        fluorescent substances (fluorophores) excited by Cherenkov        radiation) after exposure of a subject to high-energy radiation        from a radiation beam source;    -   creation of an image (e.g., image information);    -   comparative analysis of the image to a reference image; and    -   communication of the results of the comparative analysis to the        radiation beam source unit, wherein such communication is        capable of instructing modification of the beam profile. In this        way, the detected Cherenkov radiation may be used to directly        control the linear accelerator, and the beam output. Another        embodiment uses a radio-optical triggering unit (RTU) as herein        described, further provides an advanced Cherenkov-based imaging        system comprising a direct feedback interface (DFI) control        unit. In certain embodiments, a direct feedback interface (DFI)        control unit is incorporated into any system described herein.        In certain embodiments, the system includes a Cherenkov-based        imaging system including:    -   a radiation beam source which, for example, may produce a beam        cross-sectionally shaped by a beam-shaping apparatus such as a        multi-leaf collimator;    -   at least one camera capable of imaging Cherenkov radiation        (and/or radiation emitted by fluorescent substances        (fluorophores) excited by Cherenkov radiation);    -   one or more processing units that enable the control of the        radiation beam source; and    -   a direct feedback interface (DFI) control unit,    -   wherein the Cherenkov radiation is detected by the camera after        exposure of a subject to high-energy radiation from the        radiation beam source.

In certain embodiments, a beam profile based on detected Cherenkov lightor Cherenkov-stimulated fluorescence is directly fed to the radiationbeam source unit or a designer, operator, or maintainer who is testingtherapeutic radiation machine design, commissioning a newly installedtherapeutic radiation machine, or performing periodic quality auditingand/or adjustment of a therapeutic radiation machine, or who wishes forany other purpose (e.g., treatment-plan verification) to characterizethe spatial and temporal delivery of radiation by a therapeuticradiation machine to a treatment volume. In certain embodiments, a LINACmachine delivering radiation in the form high-energy electrons isdescribed as an illustrative therapeutic radiation system, but norestriction is intended by this usage; all other radiation systemscapable of inducing Cherenkov radiation in tissue are contemplated andwithin the scope of the invention.

FIG. 2 is a schematic depiction of portions of an illustrative system200 for the coordinated observation and adjustment of a device providingradiotherapy based on direct feedback control. In certain embodiments,system 200 is equipped with a subsystem interface for determining beamprofiles and dynamics by observation and analysis of Cherenkovradiation. For example, in certain embodiments, a beam-calibrationphantom 202 is placed in a zone where it is desired to measure a profileof a radiation beam 108 provided by a radiation therapy device 136. Inparticular embodiments, the zone may be a volume above or beside atreatment table (not depicted). In certain embodiments, the phantom 202is a fluid-filled tank, the fluid in the tank being a translucent ortransparent fluid having an index of refraction greater than that ofair; in a particular embodiment, the fluid is water. In certainembodiments portions of the walls of the phantom 202 are transparent toCherenkov light, e.g., the top and sides of phantom 202 consist largelyof glass or transparent plastic. In a particular embodiment, the phantom202 has sides constructed of acrylic sheets; another particularembodiment has sides constructed of polycarbonate panels. In a specificembodiment, a small amount of scattering agent and/or fluorophore isadded to the liquid in the phantom 202 to enhance scatter of Cherenkovlight without significantly affecting propagation of the radiation beam108, overcoming the inherent directionality of Cherenkov light from acollimated radiation beam and allowing more light to be detectedlaterally around the phantom 202. The system 200 may also include anapparatus for preventing interference by room lighting or may be blackedout to prevent interference of ambient light with measurements of theCherenkov radiation. However, room blackout for relatively long periods(e.g., a multi-image acquisition interval) is in general more feasiblewith a phantom 202 rather than a patient because live subjects may findblackout disturbing (e.g., claustrophobic) and workers cannot observe apatient's condition during blackout, which raises safety concerns.

In an alternative embodiment, the tank is filled with a transparentfluid such as silicone oil. In yet another embodiment, the phantom isformed from a high-index, transparent, material, such as a casthigh-index plastic, e.g., plastic water or solid water (e.g.,anthropomorphic), and may have both fluorophores and light-scatteringadditives embedded within it.

In certain embodiments, the system 200 also includes one camera or amultiplicity of cameras; the illustrative embodiment of FIG. 2 includestwo cameras 208, 210. For graphic simplicity the two cameras 208, 210are depicted as being coplanar, but in certain embodiments, the camerashave lines of sight (e.g., line of sight 212 of camera 208) that areorthogonal to each other, e.g., in a plane that is orthogonal to thetreatment beam 108. In certain embodiments, two orthogonal views sufficefor the tomographic reconstruction of the three-dimensional light fieldintensity in the emission region 214 (cross-hatched region) from eachsimultaneously acquired pair of images from the cameras 208, 210. Inparticular embodiments, where only Cherenkov light is emitted from theemission region 214, the cameras 208, 210 may lie in a plane that is atangle θ with respect to the beam 108, where cos θ=c/(nv_(p)), c beingthe velocity of light in a vacuum, n the index of refraction of thematerial filling the phantom 202 (assumed herein for illustrativepurposes to be homogeneous, but not necessarily so), and v_(p) being thevelocity of particles in the beam 108. In various other embodiments, asingle camera is arranged to move to more than one position with respectto the phantom 202, or the phantom 202 is supported in a manner thatpermits its rotation with respect to one or more cameras, or somecombination of one or more of these or other imaging arrangements isemployed to obtain sufficient information for beam profilecharacterization (e.g., tomography). In certain embodiments where thebeam 108 is known to have a radially symmetric spatial profile), asingle camera may be used to fully characterize the spatial profile ofthe beam 108. Also in other embodiments, the particle beam source 112and beam shaping subsystem 114 are attached to a gantry that enablesthem to move about a phantom 202 or a patient in the irradiation zone,delivering radiation to and from a range of angles.

The cameras 208, 210 are aimed to image at least part of the emissionvolume 214 and are coupled to a camera interface 118 of animage-processing system 120. (Camera connections to the camera interface118 may be wired or wireless and are not depicted in FIG. 2 forclarity.) In certain embodiments, the camera interface 118 captures andstores digital images from the cameras 102, 104 in memory 122 forprocessing by at least one processor 124 of an image processing system120. The processor 124 is capable of exchanging information not onlywith the camera interface 118 and memory 122 but with a timing interface126, a display subsystem 128, and potentially other devices. The displaysubsystem 128 communicates with a user interface 130 through which auser 132 can interact with the image-processing system 120. Timinginterface 126 is adapted to communicate with a system interface 134 ofthe radiation therapy device 136 to determine timing of pulses ofradiation from the beam source 112 and potentially to control pulsedroom lighting 138 to avoid interference from room lighting duringimaging of Cherenkov emissions and/or fluorescence by synchronizinglighting.

In certain embodiments, the phantom 202 is located within an environmentthat excludes significant amounts of daylight and light from otherbright source such as room illuminators. In particular embodiments, thewalls of the phantom 202 are coated on their interior surface with alight-absorbing coating except for camera viewing windows positioned infront of each camera, the coating being provided to absorb both straylight originating from outside the phantom 202 and to prevent emissionslight from being reflected from the interior walls of the phantom 202into a camera 208, 210.

In certain embodiments, a beam source 112 (e.g., particle accelerator orother device for providing high-energy radiation) is aimed to provide abeam 108 of radiation through beam-shaping apparatus 114 to phantom 202.In a particular embodiment, the beam source 112 provides a beam ofelectrons having energy of 6 million electron volts (6 MeV) or greater;in a particular embodiment, the beam energy lies between 6 and 24 MeV.In an alternative embodiment, the source 112 produces a photon beam of 6MeV or greater. In another alternative embodiment, the source 112provides a proton or heavy charged particle beam. In yet anotheralternative embodiment, the source 112 produces a beam of electrons orphotons having a substantial percentage of electrons or photons havingenergy of 1 MeV or greater. In the illustrative embodiment of FIG. 2 ,the radiation therapy device 136 is a LINAC providing a beam of 6 MEVelectrons.

Reference is now made to FIG. 1B, which schematically depicts the timingrelationships of certain embodiments of the system 100 of FIG. 1according to some methods of operation. In signal diagrams given in FIG.1B and elsewhere herein, timing relationships are not necessarily drawnto scale: e.g., the width of a pulse may be exaggerated relative to thedelay between pulses, or the duration (width) of a pulse depicted forone signal may not be proportional to that depicted for another signal.With emphasis on the sequence of events, i.e., which signals are On andwhich are Off at any given moment, Cherenkov radiation is emitted duringhigh-energy radiation beam pulses 140; timing and intensity of Cherenkovemission closely correlates to timing and intensity of radiation pulses140. Cherenkov-stimulated secondary fluorescent light 142 emitted fromnaturally occurring, artificially administered, or drug-metabolitefluorescent materials can lag the radiation beam 140 and can decayexponentially 141 after each pulse of the beam turns off, asillustrated. The time of this decay depends upon the emission lifetimeof the biochemical species that was excited.

In one illustrative mode of operation, an effective Cherenkov shutterinterval 144 that includes beam pulse 140 is used to image lightprimarily emitted by Cherenkov mechanisms, and an effective fluorescentshutter interval 146 is used to capture light emitted from the humansubject or phantom by fluorescent and/or phosphorescent mechanisms. Inthis exemplary arrangement and mode of operation, room lighting 148 ispulsed Off for the duration of Cherenkov light emission (i.e., forduration of radiation pulse 140) and fluorescent emission 142 so thatthe relatively weak optical signals of interest may not be swamped byambient light: in effect, the optical signal to noise ratio is improvedby turning room lighting 148 off during emissions imaging. If the periodof such pulses is significantly shorter than the flicker perceptionthreshold of human vision, some dimming of room lighting relative to anunpulsed mode of operation may be visible, but no irritating flickerwould be observed. In another exemplary mode of operation, room light isnot pulsed, but an intensification step of image acquisition (notdepicted) is gated On only during Cherenkov light emission, thuseffectively rejecting most of the ambient light. In an example, duringCherenkov and/or fluorescent light acquisition, light imaged by cameras102, 104 in FIG. 1A is recorded as pairs of consecutive images, with afirst image of each pair recording of Cherenkov light emitted duringbeam pulse 140 and a second image of each pair recording light emittedduring the fluorescent shutter interval 146. In certain embodiments,processor 124 of FIG. 1A executes machine-readable instructions inassociated memory, such as memory 122, to reconstruct first (Cherenkov)tomographic image sets of the subject from the first images of all imagepairs captured, to reconstruct second (fluorescence) tomographic imagesets of the subject from the second images of all image pairs captured,and to produce an image set of fluorophore distribution in the subjectbased upon some mathematical relationships (e.g., ratio) between thefirst and second tomographic image sets. In various other, similarsystems and/or modes of operation, non-tomographic imaging is performed,optionally enhanced by signal-processing steps such as backgroundsubtraction and median filtering to remove saturated pixels.

In modes of operation such as those where 5-ALA is administered, thefluorophore distribution is related to metabolic activity in thesubject, and the tomographic image set of fluorophore distribution inthe subject is indicative of metabolic activity throughout the imagedvolume of the subject. The processor 124, or a processor of anothercomputer device (not depicted), can further execute machine-readableinstructions in memory 122 to compare the tomographic image set offluorophore distribution in the subject against a tomographic image setof fluorophore distribution in the subject obtained during a priorradiation treatment session to produce a tomographic image setindicative of treatment effectiveness, i.e., changes (if any) in tumormetabolic activity.

In certain embodiments of system 100 an enclosure (not depicted herein)surrounds the subject and excludes ambient light from the subject,supporting the imaging of faint Cherenkov and fluorescence emissions.Additionally, or alternatively, the coordinated functioning of timinginterfaces 126 of system 100 (FIG. 1A) and pulsed room lighting 148(FIG. 1B) serve to mitigate or prevent interference of ambient lightingwith measurement of Cherenkov light and fluorescent light from anemission volume in the subject. The term “apparatus for preventinginterference by room lighting” as used herein shall mean either or bothof an enclosure surrounding and excluding ambient light from thesubject, and the combination of timing interfaces 126 and pulsed roomlighting 148.

In certain embodiments, Cherenkov radiation and/or associatedfluorescent emissions, which are proxies for radiation deposition byhigh-energy photons and charged particles, may be employed in spatial(i.e., one-dimensional, two-dimensional, or three-dimensional) andtemporal beam characterization or profiling. Herein, “temporal beamprofiling” refers to the characterization of variations in beamintensity over time, whether during single pulses or averaged overportions of pulses or whole pulses, and “spatial beam profiling” refersto characterization of the distribution of beam intensity across thetwo-dimensional beam cross-section, or as a function of depth in aphantom or living subject, or both. The fullest possible profile of abeam pulse, which is acquired in various embodiments, consists of athree-dimensional spatial profile re-acquired at time intervalssufficiently frequent to capture all temporal beam behavior of interestfor a given purpose: in effect, such data constitute a three-dimensionalmovie of pulse intensity, herein termed a four-dimensional beam profile.Herein, unmodified reference to a “beam profile” may denote a one-,two-, three-, or four-dimensional beam profiles.

The illustrative embodiment of FIG. 2 includes a LINAC user interface214 that is capable of exchange information with a user 132. In certainembodiments, the information thus exchanged may include settings ofcontrol parameters for beam shaping system 114, particle beam source112, movements of a gantry (not depicted) for directing the beam 108,and other measurable and/or controllable aspects of the radiationtherapy device 136, whose readings or behaviors may in general be madeknown to the user 132 and modified by the user 132. In certainembodiments, the user 132 may, in several examples, be a designermonitoring the performance of a LINAC machine under development, atechnician performing commissioning of a newly installed LINAC system, atechnician performing periodic or scheduled quality auditing and/oradjustment of the LINAC system, a technician validating the delivery ofa patient treatment plan using a phantom 202 prior to administration ofthe plan to a living subject, or a person who wishes for any otherpurpose to study and possibly adjust the temporal, spatial, and othercharacteristics of a beam 108 produced by therapeutic radiation therapydevice 136 in various modes of operation, and the interactions of such abeam with a phantom 202 and possibly with additional phantoms, livingsubjects (e.g., animal or human), or other targets.

In certain embodiments, Cherenkov-based imaging enabled by the imageprocessing subsystem 120 supports visual, qualitative, and relativequantification characterization of profiles (one, two, three, orfour-dimensional) of the beam 108, including such aspects astranslations and rotations of the beam 108, shaping of the beam 108 byvarious settings of the beam-shaping subsystem 114, changes in particleenergy (Cherenkov spectra and emission angles are both functions ofparticle energy, making such properties detectable in principle by theimaging subsystem), alterations in beam intensity (detectable becausefor a given particle energy, beam intensity and Cherenkov lightbrightness are proportional), and other aspects. Unlike methods used inthe prior art for the characterization of beam profiles, theCherenkov-based system 200 of FIG. 2 and other embodiments can acquiretwo- or three-dimensional beam profiles at rates limited only by theoptical and other technical characteristics of the cameras (e.g.,cameras 208, 210) and associated equipment (shutters, intensifiers,etc.): Cherenkov light (and/or fluorescent emissions stimulated byCherenkov light) is intrinsically a continuous, high-resolution,four-dimensional source of information about radiation flux in theirradiated volume 214. Four-dimensional characterization of individualbeam pulses is possible in various embodiments. Such data can beprocessed by the processor 124—e.g., in a tomographic manner, or usingvarious model-based and other imaging approaches that will be familiarto persons versed in the art of medical image processing—to revealfeatures of interest in one, two, three, and four dimensions (e.g.,derivative images and comparative images, delivered-dose maps) that arenot available from existing technologies. In further examples, temporalperformance of the radiation therapy device 136 can be assessed within asingle pulse, or between pulses, or during the warm-up phase ofoperation of the LINAC. This information can be used by the user 132 toadjust the performance of system 134. For example, the user 132 canissue commands to alter beam shaping by the beam-shaping subsystem 114.In another example, the user 132 or another person may make mechanicalor electrical adjustments to the beam-generating mechanism of the beamsource 112. In certain embodiments, all adjustable aspects of theoperation of radiation therapy device 136 can be adjusted in a mannerinformed by the Cherenkov-derived information collected and processed bythe image-display subsystem 128. In certain embodiments, suchinformation may be transmitted to other computing and memory devices(not depicted) for post-processing, long-term storage, studies comparingdifferent therapeutic machines or configurations, simulation, and otherpurposes. Advantageously, certain embodiments enable the rapid,high-resolution, four-dimensional characterization of radiation deliveryto the phantom 202, without need to reposition the cameras 208 210 orthe phantom 202, as well as adjustments of radiation therapy device 136in a manner informed by such detailed and timely characterization.

Moreover, certain embodiments enable efficient positioning of a phantom202, or of other targets, with respect to the isocenter of the LINAC 136(or other pulsed therapeutic therapy device), in order that beamcharacterization or other tasks may be performed. In certainembodiments, the therapeutic radiation system indicates its isocenterlocation using intersecting visible lasers. In various embodiments,these lasers can be imaged by the same cameras (e.g., cameras 208 and210) that are used to image Cherenkov and/or fluorescent light. Softwarecontrol and feedback as described herein (e.g., through the systeminterface 134 and image processing subsystem 120) provide isocenteralignment information to the user 132. In a particular example,isocenter alignment laser images may be compared to physical or virtualregistration marks on the phantom 202 as imaged to the user 132, and thephantom's position is adjusted accordingly: for example, control ofplatform positioning of the radiation therapy device 136 is conductedthrough the system interface 134, either manually by the user 132 or asdetermined by software computed by the image processing subsystem 120 oranother computing device, to produce satisfactory alignment of isocenterof the phantom 202 or a region or target therein. Such embodimentsminimize the time required for phantom setup and offer, for example,advantageous time savings for quality audit processes compared tolower-resolution electronic beam-locating systems. Because the camera orcameras of various embodiments have relatively very high spatialresolution and can be dual-used for both laser observation and Cherenkovobservation, embodiments have a flexibility of set-up which exceeds thatof known electronic diode or ionization chamber ionization processes.

In certain embodiments, the user interfaces 130 and 214 are supplementedor replaced by direct informatic communications interfaces and the humanuser 132 is supplemented or replaced by a computational system, such asa software program or artificial intelligence, that is configured toexchange information with image-processing subsystem 120, with thesystem interface of the radiation treatment device 136, and potentiallywith other measuring devices, mechanical systems, computing devices, andother devices or systems. In such embodiments, the software program orartificial intelligence performs some or all the functions ofevaluation, comparison, and adjustment that in the embodiment of FIG. 2are performed by the human user 132.

In certain embodiments the operation of system is as illustrated by theflowchart of method 300 of FIG. 3 , adjustment of the radiation therapydevice 136 is performed to produce a beam of desired characteristicswithin a specified accuracy range. In a preliminary positioning step 302that may entail imaging of the system isocenter, the phantom 202 may bepositioned within the treatment space of the radiation therapy device136 so that the center of the phantom 202, or some other point withinthe phantom 202, is located at the system isocenter. In abeam-programming or adjustment step 304, the radiation therapy device136 may be set to produce a beam 108 of a given character forirradiation of the phantom 202: such characteristics as intensity, pulseduration, pulse frequency, number of pulses, and two-dimensional beamprofile as determined by the beam-shaping subsystem 114, among othercharacteristics, may be set to predetermined values. The predeterminedvalues may be specified to serve a manufacturer's test plan, or as partof a patient treatment plan, or according to other criteria. In anirradiation step 306, one or more pulses of radiation are supplied bythe radiation therapy device 136, while imaging (e.g., stereoscopicgated imaging) of the Cherenkov light and/or secondary fluorescent lightinduced in the phantom by the radiation is performed. In animage-processing or beam-profile calculation step 308, data from thecameras 208, 210 is processed by the image processing subsystem 120 toproduce, in this illustrative method, a two-dimensional irradiationpattern or beam profile at the system isocenter. In a display andcomparison step 310, an expected profile and the observed profile arecompared. Such comparison may be visual and ad hoc, or quantitative, ormay combine several modes of comparison: in any case, such comparisonproduces a judgement, whether ad hoc or numerical, as to whether theexpected irradiation pattern is sufficiently like the observed radiationpattern or not. If it is sufficiently similar, then the method mayproceed to the testing 316 of another configuration of the radiationtherapy device 136 or may terminate. If agreement between expected andobserved radiation is unsatisfactory, then an adjustment step 312 isperformed, in which one or more adjustable aspects of the mechanismand/or operation of the radiation therapy device 136 is performed by oneor more of the user 132, software, or an additional person. In a loopingor convergence phase 314, irradiation and observation 306, beam profilecalculation 308, comparison 310, and possibly adjustment 312, asdescribed above, are repeated until satisfactory agreement betweenexpected and observed radiation delivery is observed, a different systemconfiguration is set up for testing 316, or the operator elects to endthe procedure 318.

The calibration method 300 is illustrative of a broad class ofprocedures and methods by which the system 200 or various otherembodiments may be operated. The systems and methods of most embodimentsentail rapid and information-rich feedback to characteristics of theradiation therapy device 136 based on observed and processed Cherenkovlight or secondary fluorescence induced in the phantom 202 by theradiation beam 108.

C. Enhanced Beam Characterization: Integration of Cherenkov andNon-Cherenkov Sensing

Another embodiment provides high resolution dose quantifiedCherenkov-based images, through enhanced beam characterization. Certainembodiments use a radio-optical triggering unit (RTU), further addressthe challenges of fast 3D dosimetry utilizing a technique that allowsfor real-time dose imaging, e.g., in water phantoms. While knownnon-Cherenkov radiation measurement devices, such as external portalimaging devices (EPID), can provide a 2D transverse distribution of atransmitted beam, and the Cherenkov imaging provides an accurate lateralview of the dose; the tools and methods described herein provide theintegration of these measures by providing for the simultaneousacquisition of EPID images and lateral Cherenkov images. In certainembodiments, the integration of these measures produces a consistent 3Ddistribution of the deposited dose. In particular embodiments thenon-Cherenkov radiation measurement device, e.g., EPID, and theCherenkov techniques provide images with high frame rates (˜10 fps)which permits real-time 3D beam reconstruction. As such, and inparticular embodiments, this affords the ability to performpre-treatment plan verification and quality assurance due to the highspatial and temporal resolution of the measured 3D dose distributionsproduced.

Traditionally, measurement methods for therapeutic radiation beams havedepended on radiographic or Gafchromic film dosimetry for obtainingplanar two-dimensional (2D) dose distributions inside a dosimetryphantom placed inside the treatment zone. Although film dosimetry ishigh-resolution, the process is cumbersome, not real-time, and mayexhibit processing-dependent variability. Other known techniques includeelectronic portal imaging devices (EPIDs), ionization chamber arrays,and semiconductor arrays. For example, Theraview Technology's EPIDimages over a 40×40 cm square planar array with 1024×1024 pixels and12-bit acquisition. A digital analogue to film dosimetry, EPID imagingis easy to use—EPIDs can be integrated with therapeutic systems andsoftware-controlled—but the true experimental measurement may only bemade at a single planar slice: thus, for EPIDs and other planar-typedosimetry methods, fully three-dimensional beam characterization isdifficult and time-consuming to perform or may be impossible, while beamcharacterization in 3D over time (herein referred to as“four-dimensional” characterization) is extremely difficult and rarely,if ever, performed. Also, planar array-based systems have inherentlylimited resolution due to the finite spacing of the detectors.

Additional dosimetry methods currently under development include gel andplastic or liquid scintillation dosimetry. Despite several advantages,gel dosimetry is time consuming and requires post-processing and areadout mechanism such as optical computed tomography or magneticresonance imaging, while scintillation methods require carefulcalibration and suppression of the stem effect. Finally, none of thecurrently known techniques are truly water equivalent, as the activemedium is not water itself, which is of importance, as water is thegold-standard dosimetry medium due to its radiological close equivalenceto tissue, cheap abundance, high purity, and ease of interinstitutionalstandardization.

As such, another embodiment uses a radio-optical triggering unit (RTU),to provide a quantifier integration (QI) unit to perform a methodcomprising:

-   -   detection of Cherenkov radiation (and/or radiation emitted by        fluorescent substances (fluorophores) excited by Cherenkov        radiation) after exposure of a subject to high-energy radiation        from a radiation beam source, and establishment of a Cherenkov        radiation image;    -   detection of non-Cherenkov radiation after exposure of a subject        to high-energy radiation from a radiation beam source, and        establishment of a non-Cherenkov radiation measurement; and    -   integration of the non-Cherenkov (i.e., quantitative) radiation        measurements (e.g., from an ionization chamber or an EPID) with        the Cherenkov radiation image (e.g., tomography), to produce a        quantitatively calibrated high-resolution Cherenkov image. The        language “high resolution” as used herein describes high spatial        and temporal resolution of the measured dose distribution, e.g.,        three-dimensional dose distribution. The quantitatively        calibrated Cherenkov images represent beam geometry and        intensity that are labeled with absolute dose units. These        images may be used to establish a calibration where a given        intensity of Cherenkov light at a given point of the phantom is        experimentally associated with a particular intensity of        ionization radiation in absolute dose units as measured by, for        example, an EPID or ionization chamber. Further, in particular        embodiments, non-Cherenkov radiation measurements (such as        ionization chamber measurements) at sampling of discrete        locations within the phantom or treatment volume (e.g., along        the beam axis) can be used to produce a table or map (one-,        two-, or three-dimensional) of local conversion factors that        link units of observed Cherenkov brightness to absolute dose        units in different portions of a beam.

In certain embodiments of the quantifier integration (QI) unit, thenon-Cherenkov radiation measurement device is selected from the groupconsisting of an ionization chamber, EPID, diodes, and any combinationthereof. In certain embodiments, the method may further comprise thestep of communication of the quantitatively calibrated high-resolutionCherenkov image to the radiation beam source unit. In this way, incertain embodiments, the detected Cherenkov radiation may be used todirectly control the linear accelerator, and the beam output. In certainembodiments, the quantitatively calibrated high-resolution Cherenkovimage may be stored on a second a machine-readable medium (e.g., whereinthe second machine-readable medium is the machine-readable medium of aDFI control unit). In certain embodiments, the non-Cherenkov radiationmeasurements allow quantitative estimation of the depth-vs.-dose curvefrom the Cherenkov radiation image.

Another embodiment provides an advanced Cherenkov-based imaging systemutilizing a radio-optical triggering unit (RTU), including a quantifierintegration unit. In certain embodiments, a quantifier integration (QI)unit may be incorporated into any system described herein. In certainembodiments, an advanced Cherenkov-based imaging system includes:

-   -   a radiation beam source (e.g., a particle accelerator or other        device for providing high-energy radiation, which, for example,        may be cross-sectionally shaped by a beam-shaping apparatus,        e.g., a multi-leaf collimator);    -   at least one camera capable of imaging Cherenkov radiation        (and/or radiation emitted by fluorescent substances        (fluorophores) excited by Cherenkov radiation);    -   one or more processing units that enables the control of the        radiation beam source;    -   a non-Cherenkov radiation measurement device; and    -   a quantifier integration unit,    -   wherein the Cherenkov radiation is detected by the camera and        non-Cherenkov radiation is detected by the non-Cherenkov        radiation measurement device after exposure of a subject to        high-energy radiation from the radiation beam source.

Alternatively, in certain embodiments, the quantifier integration unitis implemented and integrated into an existing system via a supplementalkit, including for example, the quantifier integration unit and anycomponent of the system described herein not present in the existingsystem to which the kit will be added.

Reference is now made to FIG. 4A, which schematically depicts portionsof an illustrative system 400 according to certain embodiments. System400 resembles system 200 of FIG. 4A but with the addition of anon-Cherenkov radiation measurement device 502. In certain embodiments,the non-Cherenkov radiation measurement device is an ionization chamber.For example, a typical ionization chamber is a gas-filled chamber inwhich high-energy (ionizing) radiation creates free charges that can bedetected and whose rate of appearance corresponds to the intensity ofhigh-energy radiation within the ionization chamber. The term“ionization chamber” is often applied to denote entire radiation-probesystems that include an ionization chamber, not only to the chamber perse. Ionization chamber probes are generally considered the gold standardfor calibration of therapeutic radiation systems because they give aprecise and highly localized measure of the ionizing radiation deliveredby a therapeutic system at a given point, e.g., a point within awater-filled phantom. In particular embodiments, the ionization chamberis the cylindrical, waterproof Farmer-type ion ionization chamber, whichis recommended by various dosimetry protocols for dose measurement ofradiotherapy beams. The chambers of such probes typically have volumesof 0.6-0.65 cm³ and can report measured calibrated exposure accurate toNational Institute of Standards & Technology (NIST) certified standards,which can be directly mapped to dose delivery at that point. The valueof having one or more measures of exposure or dose allows calibration ofthe Cherenkov intensity into similar intensity units.

In certain embodiments, measurements from ionization chamber arecombined/integrated with Cherenkov imaging (e.g., tomography) to produceaccurately calibrated Cherenkov images or non-image measurements. Incertain embodiments, a localized, highly precise measurement ofradiation intensity is obtained by an ionization chamber at a givenpoint (e.g., a point inside a water-filled phantom), the ionizationchamber is removed, and the intensity of Cherenkov light emitted underidentical radiation conditions by the sub-volume of the phantomcorresponding to that previously occupied by the ionization chamber isobserved. (This order of events may be varied; e.g., Cherenkov imagingmay precede ionization chamber measurement.) A calibration is thusenabled by which a given intensity of Cherenkov light at a given pointof the phantom is experimentally associated with a particular intensityof ionization radiation as measured by ionization chamber in absolutedose units. Ionization chamber measurements at sampling of discretelocations within the phantom or treatment volume (e.g., along the beamaxis) can be used to produce a table or map (one-, two-, orthree-dimensional) of local conversion factors that link units ofobserved Cherenkov brightness to absolute dose units in differentportions of a beam. In an example, the resulting mapping of units isdepth-dependent; in another example, the mapping is dependent on depthand on radial distance from beam center; in another example, the mappingis dependent on depth, radial distance from beam center, and distancefrom beam center. Thus, in certain embodiments, the tools and methodsherein described enable the production of Cherenkov images of beamgeometry and intensity that are labeled with absolute dose units, notmerely with units of optical brightness.

In certain embodiments, for example in the illustrative system 400 ofFIG. 4A, the non-Cherenkov radiation detection device 402 is aFarmer-type ionization probe inserted into the liquid-filled phantom202. The actual gas chamber 404 of the probe 402 is at one tip of theprobe 402. In particular embodiments, the volume of the chamber 404 ispresumed to be sufficiently small relative to the irradiated volume 214to permit meaningfully localized characterization of beam 108 intensity.

FIG. 4B depicts a closer view of one embodiment of the phantom 202 andprobe 402, omitting cameras and other apparatus for clarity. In oneillustrative method of operation of the system 400, the probe 402 may bemoved so that the ion chamber 404 occupies a series of positions alongthe axis of the beam 108. In FIG. 4B, these points (e.g., position 406)are depicted as evenly spaced along a line and seven in number, but ingeneral need not be evenly spaced and may be of any number or spatialarrangement. In certain methods of operation, either the entire phantom202 may be moved along the axis of the beam 108 or the location of thechamber 404 may be moved. For clarity, only positions of the chamber404, not the whole probe 402, are depicted in FIG. 4B.

In certain embodiments, and in the illustrative method partlyillustrated in FIG. 4B, ionization chamber measurements of radiationintensity are made centrally along the axis of beam 108. In certainembodiments, after all measurements, the probe 402 is removed from thephantom 202 and one or more Cherenkov images (i.e., images of Cherenkovlight or secondarily emitted fluorescent light) of the irradiationvolume 214 are acquired. The average intensity of the observed lightfrom within each of the seven measurement volumes is then directlycorrelated with radiation intensity as measured by ionization chamber.In one example, a continuous one-dimensional calibrative function can becalculated (e.g., by interpolation) from the discretely measuredcorrespondences of radiation intensity to light intensity and applied tosubsequent Cherenkov images of the phantom to accurately associateradiation intensity units with light-intensity units. In certain othermethods of operation, radiation intensity measurements may be madewithin the irradiation volume 214 according to various geometric schemesother than or addition to that depicted in FIG. 4B (e.g., measurementsmay be located to sample a planar cross-section, or more than one planarcross-section, or a given sub-volume of the irradiation volume 214, ormultiple one-dimensional transects like that depicted in FIG. 4B).

Certain embodiments advantageously combine the features of ionizationchambers or other high-precision radiation tools with those of Cherenkovimaging. Ionization chamber dose measurements are highly accurate butslow and typically not acquired in more than one dimension (e.g., alongbeam axis for depth versus dose curves, or orthogonally to beam axis forbeam profile measurements) at a time. In comparison, Cherenkov imaginghas the inherent strengths of rapidity and provision of two-, three-,and four-dimensional data very quickly. Cherenkov imaging does, however,require calibration for quantitative accuracy of dose estimation. Usingthe tools and methods described herein, combining the two types ofmeasurements—i.e., high-accuracy point or small-volume dose measurementsand Cherenkov imaging—allows exploiting the strengths of both modalitieswhile mitigating their weaknesses.

Reference is now made to FIG. 5 , which schematically depicts portionsof an illustrative system 500 according to certain embodiments. System500 resembles system 200 of FIG. 2 but with the addition of anon-Cherenkov radiation measurement device 502. In one example, theimaging device 502 is an external portal imaging device (EPID). One typeof EPID consists essentially of a converter layer that converts incidentradiation into light and a two-dimensional array of electronic sensorscapable of sensing the light thus produced. In certain embodiments, theconverter layer may consist essentially of some form of metal plate incontact with either an ionization medium or a phosphor screen. Further,in certain embodiments, the detection array may be in a camera trainedupon the converter, or in extended solid-state array (active matrix flatpanel) parallel and close to the converter. In some EPID technologies,conversion is omitted in favor of direct detection by active matrixflat-panel devices. In essence, an EPID serves as a piece of electronicfilm whose image may be retrieved, in the form of digital data, atrelatively high speed and without the need for development.

Regardless of technological basis, a typical EPID is capable of imaginga rectangular two-dimensional cross-section of the beam 108 (typicallyorthogonal to the beam 108) at a given distance from the beam source112. In one illustrative system 500, data from the EPID may be routed tothe memory 122 and processor 124 of the Cherenkov image processingsubsystem 120, e.g., via a quantifier integration unit described herein;in certain alternative embodiments, EPID data may be separatelyprocessed through a different interface, memory, and processing system(not depicted), such as is already provided in an integral manner withsome LINAC or other therapeutic-radiation systems, before being routedto or integrated with the Cherenkov image processing subsystem 120.Provisions for mounting, moving, and communicating with the EPID are forsimplicity omitted from FIG. 5 , but the nature of such provisions willbe familiar to persons versed in the construction of such devices,considering the disclosure herein.

Certain embodiments employ one or more non-Cherenkov measurementdevices, which may employ one or more sensing modalities (e.g.,ionization, direct-detection flat panel), to acquire beam information.In one example, the EPID of FIG. 5 acquires lateral beam information,i.e., one- or two-dimensional radiation intensity information in theplane of the non-Cherenkov device, which is orthogonal to the beam 108.In addition to non-Cherenkov dose information, Cherenkov emissioninformation is acquired from one or more viewpoints, e.g., by a movingcamera, or a camera fixed relative to a moving irradiation target, or bya multiplicity of cameras. Thus, in certain embodiments, information ondelivered dose is obtained from a plurality of viewpoints using at leasttwo distinct sensing modalities, one of which is Cherenkov imaging. Inone example, the lateral profile or extent of the beam at the back ofthe treatment area (i.e., in the position of the EPID 502 depicted inFIG. 5 ) can be measured and, with assumptions based on lateral beamdivergence and penumbra, estimates of the three-dimensional image ofbeam 108 can be made. This information, combined with axial decay of thesignal from lateral Cherenkov imaging, can be used to estimate fullfour-dimensional dosimetry in a water tank or other phantom.

Advantageously, the system enables measurements to be made in real time,allowing characterization of phantom-delivered complex treatment plansat all points in the treatment. This can be a valuable tool for routinepatient plan verification prior to delivery in the patient; verificationcould be performed on each plan prior to delivery. This is especiallyimportant for complex treatment plans, where verification is not onlynecessary but is reimbursed by some systems of health-care funding(e.g., by Medicare in the US, as “pretreatment simulation”).

In addition, in certain embodiments of the system, the EPID or othernon-Cherenkov imaging information is combined with Cherenkov imagingacquired during actual patient irradiation. Although Cherenkov lightcannot typically be detected from deep within human tissue, surficialCherenkov light may be imaged as a proxy for skin dose. In effect,Cherenkov light emitted at or just below the skin surface upon beamentry serves as a cross-sectional (through the generally non-planar skinsurface) image of the incident beam, conveying information both onintensity profile and overall geometry: this information can be combinedwith beam profile data transmitted through the medium and detected byEPID or other non-Cherenkov information using a variety of mathematicalmodeling procedures to produce estimates of internal patient dosegeometry, and in certain embodiments, with high temporal resolution,that are more accurate than those achievable from either Cherenkov ornon-Cherenkov sensing alone. It is advantageous for patient safety andtreatment efficacy to have improved knowledge of internal dosagegeometry.

III. Methods of Cherenkov-Based Imaging

We provide methods using a radio-optical triggering unit (RTU). Suchmethods include, methods of radio-optical triggering comprising:

-   -   detection of scattered radiation by a fast response time        scintillator (SCI) coupled with a high speed, single photon        sensitive, silicon photomultiplier module (SiPM)) upon exposure        of a subject to high-energy radiation from a radiation beam        source;    -   conversion and amplification of the scattered radiation into        optical photons, generating an analog electrical signal;    -   processing the analog signal to a digital timing signal, wherein        the digital timing signal is synchronized with the radiation        beam source; and    -   communication of the digital timing signal to trigger the        operation of at least one camera capable of imaging Cherenkov        radiation,    -   such that the operation of said camera is triggered to detect        Cherenkov radiation for Cherenkov imaging purposes.

Versatile RTU

With reference to FIGS. 11, 12, and 13 , a versatile RTU 1000 includes afast-response radiation detector 1002. In an embodiment, thefast-response radiation detector 1002 uses a fast-response scintillatorcoupled to a fast-response photodetector, in an alternative embodimentthe fast-response radiation detector 1002 is a semiconductor radiationdetector. The fast-response radiation detector 1002 provides a rawoutput 1016 synchronized to pulses of the radiation and which may beused as above described to trigger cameras to detect Cherenkovradiation.

Signals from the fast response radiation detector 1002 are not welltimed for detecting background images or fluorescent images, in additionthere may be shutter delays and risetime delays. In an embodiment,signals from the fast response radiation detector 1002 are detected 1050and measured 1052 as to time 1030 of occurrence, and width 1032 by pulsetiming and measurement circuits 1004, providing this information toprocessor 1008. Processor 1008, operating under control of machinereadable instructions of firmware in memory 1010, determines a pulserate and pulse width from the time of occurrence of multiple radiationpulses, and predicts 1054 a time 1024 of occurrence for each nextradiation pulse, instructing pulse generator circuits 1006 to generate1056 a synchronized pulse 1028 output 1018 during each next radiationpulse. Processor 1008 also instructs pulse generator circuits 1006 toprovide a signal 1022, bearing a pulse 1023 just after an end of theradiation pulse to be used for imaging fluorescent emissions before theydecay, and an output 1020 bearing a pulse 1021 late in eachpulse-to-pulse interval to trigger capture of background images forbackground subtraction.

To prevent interference by room lighting, when the fast responseradiation detector 1002 incorporates a scintillator and photodetector,those components are encapsulated in a light shield 1014 configured toexclude light from other sources. Further, to prevent stray or scatteredhigh energy radiation or x-rays from erasing data inelectrically-programmable or reprogrammable memory devices, orcorrupting data in dynamic RAM memory devices, of memory 1010, memory1010 is enclosed in radiation shield 1012.

Unintensified, Multi-Pulse-Integrating Camera

Due to the weak efficiency of Cherenkov light generation, the surfacefluence ranges from 1-100 nW/cm2, and therefore is not easily observedunder the standard treatment conditions. However, the pulsed nature ofthe beam can be leveraged to suppress the background and improvesignal-to-noise ratio using synchronized gated imaging. In mosttherapeutic LINAC systems, the radiation dose is delivered to thepatient in a form of a sequence of x-ray or electron pulse bursts withmicrosecond pulse duration and with millisecond repetition rate. In pastsystems, a gated image intensifier coupled with CCD or CMOS imagingsensors was the sole technology capable of suppressing thebackground-only light while amplifying the weak Cherenkov light duringthe microsecond gating periods. The amplified image from the gated imageintensifier was imaged by a CCD or CMOS photodiode-array imaging sensor.In addition to requiring high voltages and vacuum for operation, theimage intensifier portions of these cameras were found to exhibitlong-term non-linearity and high sensitivity to stray x-ray noise, whichis abundant in the treatment room and caused unwanted image artifacts.

We discovered that a commercial-grade time-domain Time-of-Flight (ToF)CMOS image sensor, the Teledyne e2v BORA® (trademark of TeledyneTechnologies, Thousand Oaks, California) 1.3-megapixel image sensor, canbe configured as a pulse-gated, multi-pulse integrating, image sensor ina way to be capable of detecting Cherenkov light from tissue. It isexpected that similar image sensors may become available with greaternumbers of pixels. The BORA ToF image sensor is operated in a gatedmulti-integration mode, where the photo-sensitive component (photodiode1502) (FIG. 15 ) of the pixels is repeatedly connected (gated) by atransfer gate 1506 to a storage node (capacitor 1504) within each pixelduring each beam pulse, and both isolated from the storage node andprecharged by a precharge gate 1508 between beam pulses to preventtransferring charges accumulated on the photodiode from backgroundillumination between beam pulses from reaching the storage node. Theelectronic signal from a multitude of light pulses is stored on thestorage node 1504 in the pixels prior frame readout. Accumulation of thesignal in pixels prior readout helps overcome the readout noise whenreading a Cherenkov or scintillation image acquired during beam pulsesby integrating the dim Cherenkov or scintillation light over multiplebeam pulses while excluding that portion of background light that isreceived between beam pulses.

Additionally, the gated operation also allows to be used to recordbackground light received between beam pulses only. This is achieved byintroducing a phase shift or delay between the X-ray or electron pulses,and the gate signal to acquire light from the treatment zone and patientunder background illumination with the beam off. Background-onlyacquisition of a background correction image frame allows subtraction,as controlled by firmware in the DSP, of the background light from theCherenkov or scintillation image in the DSP. This allows quantitativeimaging and remote dose measurement even in the presence of arbitrarybackground light from room lighting; imaging with room lights on isdesired by many patients because they can become claustrophobic whenleft in a strange room in the dark.

The general imaging setup is depicted if FIG. 1A. Subject 106 isirradiated by a beam of X-rays or electrons 108, generated in a pulsedlinear accelerator (LINAC serving as beam source 112. Cherenkovemissions are emitted from tissue, and scintillation light is emittedfrom scintillator, if present. One or more cameras 102, 104, which usesthe gated BORA CMOS ToF image sensor array and a lens system, observesthe beam interaction area of the patient. The gating signal is driveneither by directly interfacing the LINAC, or by using a remote triggerdetector RTU as described above, for a trigger signal to which the gatesignal is synchronized. Gated images are processed in the camera andimage processing subsystem 120, which also displays thebackground-subtracted Cherenkov or scintillation image and relatedmetrics.

In one embodiment, the architecture of single pixel in a gated CMOSlight sensor array is depicted in FIG. 15 , and operates according tothe corresponding timing diagram is outlined in FIG. 16 . Image frameacquisition begins with resetting the charge of storage capacitor 1504 Cby applying a “reset” pulse to a reset device 1510, typically chargingthe capacitor to a reference voltage Vr. During the gated exposure ofthe Cherenkov or scintillation frame, the gate pulse gate 1604 isrepetitively applied to the sensor during beam pulses 1602 to allowphotocurrent flow from photodiode PD and transfer gate 1506 to collectas charge on capacitor 1504. To erase stray charges accumulated betweenbeam pulses on photodiode PD 1502, the buffer signal 1608 may be used toturn on a precharge gate transistor 1508 to precharge the photodiode PD1502. Once charge from a suitable number of radiation pulses haveaccumulated on the storage capacitor 1504, charge on the storagecapacitor 1504 is read through source follower 1512 and selection 1514transistors by a select line 1610 to a data readout line.

This action substitutes for the combination of image intensifier gatingand a single exposure in conventional Cherenkov cameras. Once light isacquired for a necessary number of pulses is acquired, the gate line isset inactive, and the 2D charge matrix is read out as described throughthe source follower 1512 and selection transistors 1514. In embodiments,light is acquired during at least ten to twenty pulses but in someembodiments light may be acquired and integrated during as many as 200or more beam pulses for each image.

The concept of intensifier-less Cherenkov imaging was demonstrated usinga 1.3-megapixel Teledyne BORA ToF sensor and an optical lens in a cameraimaging a square 6MV X-ray beam intersecting a white ABS plate andcaptured at a rate of 20 frames per second. A representative singleframe of an image stream capturing Cherenkov radiation is shown in FIG.17 . A static background frame was captured prior to capturing theCherenkov frame, subtracted from the Cherenkov frame, and the resultingCherenkov-only image is displayed in FIG. 17 in light color 1700, whilethe background image is displayed in grayscale.

FIG. 19 is an exemplary integrated background image of a target 1900captured over 200 beam pulses. FIG. 18A is an exemplary single-frameimage of Cherenkov radiation corrected by subtracting the integratedbackground image of FIG. 19 ; FIG. 18B is an exemplary image ofCherenkov radiation captured with a gated, multiple-pulse-integrating,CMOS image sensor over 200 beam pulses corrected by subtracting anintegrated background image of FIG. 19 , showing the significantimprovement in image quality over the single-frame photograph of FIG.18A attainable with the BORA ToF image sensor array operated in thepulse-gated, multiple-pulse integrating (PG-MPI), mode herein describedand showing a region 1800 of a target emitting Cherenkov radiation wherea pulsed radiation beam intersects the target.

Advantages of the system and method herein include that themulti-integration mode of a gated time-of-flight imaging sensor, hereinknown as a pulse-gated, multiple-pulse-integrating, CMOS image sensor orcamera can image the weak Cherenkov and/or scintillation light with aperformance and image quality sufficient for commercial application. Oursystem eliminated image artifacts and signal nonlinearity caused byimage intensifiers. Further, the complexity of the Cherenkov camera isdecreased over prior systems, as there is no need of a fragile, complex,and expensive image intensifier. The commercially-available image-sensorchip that we used in this demonstration allowed nearly 100-fold pricereduction of the imaging system, and holds significant potential forcommercialization of Cherenkov cameras for safety applications inradiotherapy.

We anticipate better images may be obtained by cooling the image sensor.

In summary, the system is operated according to a radiation exposuredetermination method 2000 (FIG. 20 ) where the pulsed radiation beamsource 112 (FIG. 1A) provides 2002 a regularly-spaced sequence of pulsesof a radiation beam 108 to tissue 110 of the subject 106. In embodimentsusing the radio-optical triggering units (RTUs) illustrated withreference to FIG. 6A or 6B, scattered radiation from pulses of theradiation beam 108 is detected 2004 in a high-speed radiation detectorof the RTU to provide a signal “A”. In some embodiments using dual RTUsas illustrated with reference to FIG. 6B, scattered radiation frompulses of the radiation beam is detected in a second high-speedradiation detector to provide 2006 a second signal “B”, signals “A” and“B” are then logically “AND”-ed to generate a composite radiationdetection signal “C. As illustrated with reference to FIG. 13 , thecomposite signal “C” in dual RTU systems, the signal “A” in single RTUsystems, or a pulse output of the pulsed radiation beam source insystems without an RTU is processed to measure time and duration ofpulses and to generate 2008 a “beam-ON” pulse signal.

The PG-MPI camera is then reset 2012 and the “beam-ON” signal used totrigger the PG-MPI camera to integrate 2014 received Cherenkov lightreceived from tissue 110, the Cherenkov light emitted during pulses ofthe pulsed radiation beam, the Cherenkov light being integrated in thePG-MPI camera over a sequence of multiple pulses of the pulsed radiationbeam, while ignoring light received between pulses of the pulsedradiation beam, to generate a Cherenkov light image. In someembodiments, the Cherenkov light is integrated over at least 10 and insome embodiments at least 200 pulses of the pulsed radiation beam whileforming the Cherenkov light image.

As discussed with reference to FIG. 13 , a “Beam OFF” signal is alsogenerated 2010, the “Beam OFF” signal being timed to be between, and notoverlapping, pulses of the radiation beam, this signal may be derivedfrom RTU output signals A or C, from the “beam ON” signal, or directlyfrom a signal provided by the pulsed radiation beam source 112 asappropriate for the system. The PG-MPI camera is then reset 2016 and thePG-MPI camera is used to generate 2018 a background image of lightreceived from tissue of the subject when pulses of the radiation beamare not present and thus no Cherenkov light is being emitted from tissueof the subject.

The background image is scaled if necessary and subtracted 2020 from theCherenkov light image to generate 2024 a corrected Cherenkov lightimage.

Separately, a set of calibration tables has been generated 2022, inembodiments these calibration tables are generated using anon-Cherenkov-based dose-quantifier device or system; these tables needonly be generated once and can be reused for converting many correctedCherenkov light images to dose maps.

The calibration tables are then used with overall beam pulse counts toconvert 2024 the corrected Cherenkov light image into a calibratedcurrent dose map and a calibrated cumulative dose map. Generation ofthese dose maps may be repeated many times during a radiation treatmentsession. Once generated, the calibrated current and calibratedcumulative dose maps may be displayed 2026 to a user or operator toverify correct treatment is being applied to the subject, orautomatically compared against thresholds and alarms generated whenevera dose map shows areas of excessive dose.

Combinations

The features herein described can be combined in a multitude ofdifferent ways while forming various embodiments of the system. Amongcombinations anticipated by the inventors are:

A Cherenkov imaging system designated A including a high-speed radiationdetector configured to provide a first timing signal synchronized withpulses of radiation provided by a pulsed radiation beam source; thetiming signal being coupled to control operation of at least one cameracapable of imaging Cherenkov radiation; and a digital image-processingsystem; where the high-speed radiation detector is selected from thegroup consisting of solid-state radiation detectors and radiationdetectors of the type comprising a scintillator and a photodetector; andwhere the at least one camera capable of imaging Cherenkov radiation isa pulse-gated, multiple-pulse-integrating, (PG-MPI) camera synchronizedthrough the digital time signal to pulses of the radiation beam.

A Cherenkov imaging system designated AA including the Cherenkov imagingsystem designated A wherein a plurality of pixels of the PG-MPI cameracomprises a photodiode coupled through a precharge gate to a prechargelevel signal, the photodiode also coupled through a transfer gate to acapacitor associated with the storage node, the storage node alsocoupled through a reset transistor to a reset voltage signal, thestorage node also coupled to a gate of a source follower, the source ofthe source follower being coupled through a select transistor to a datareadout line.

A Cherenkov imaging system designated AB including the Cherenkov imagingsystem designated A or AA further comprising a second high-speedradiation detector configured to provide a second timing signal, and thecamera capable of imaging Cherenkov radiation is controlled to imageCherenkov radiation when both the first and second high-speed radiationdetectors detect radiation.

A Cherenkov imaging system designated AC including the Cherenkov imagingsystem designated AB, AA, or A wherein the digital image-processingsystem is configured to use the PG-MPI camera to capture an image ofCherenkov emissions and a background image, and to subtract thebackground image from the image of Cherenkov emissions to generate acorrected Cherenkov image.

A Cherenkov imaging system designated AD including the Cherenkov imagingsystem designated AC wherein the digital image-processing system isfurther configured to apply calibration tables to the correctedCherenkov image to generate a dose map.

An imaging unit designated B and including a trigger input adapted forconnection to a beam-on output signal provided by a pulsed radiationbeam source, the trigger input receiving a digital timing signal;apparatus configured to communicate the digital timing signal to triggeroperation of at least one camera capable of imaging Cherenkov radiation;where the camera capable of imaging Cherenkov radiation is apulse-gated, multiple-pulse-integrating, (PG-MPI) camera synchronizedthrough the digital time signal to pulses of the radiation beam source.

A Cherenkov imaging system designated BA including the system designatedB wherein each pixel of a plurality of pixels of the PG-MPI cameracomprises a photodiode coupled through a precharge gate to a prechargelevel signal, the photodiode also coupled through a transfer gate to acapacitor associated with the storage node, the storage node alsocoupled through a reset transistor to a reset voltage signal, thestorage node also coupled to a gate of a source follower, the source ofthe source follower being coupled through a select transistor to a datareadout line.

A Cherenkov imaging system designated BB including the system designatedB or BA wherein the digital image-processing system is configured to usethe PG-MPI camera to capture an image of Cherenkov emissions and abackground image, and to subtract the background image from the image ofCherenkov emissions to generate a corrected Cherenkov image.

A Cherenkov imaging system designated BC including the system designatedBB wherein the digital image-processing system is further configured toapply calibration tables to the corrected Cherenkov image to generate adose map.

A method of imaging Cherenkov light emitted by a phantom or tissuedesignated C includes providing a timing signal synchronized to pulsesof a pulsed radiation beam; applying the pulsed radiation beam to thephantom or tissue, the pulsed radiation beam causing the phantom ortissue to emit the Cherenkov light; imaging the Cherenkov light with apulse-gated, multiple-pulse-integrating, (PG-MPI) camera; imaging theCherenkov light being performed by integrating light received by thePG-MPI camera during multiple pulses of the radiation beam and notintegrating light received by the PG-MPI camera between pulses of theradiation beam.

A method of imaging Cherenkov light designated CA including the methoddesignated C where the timing signal synchronized to pulses of thepulsed radiation beam is provided by a radio-optical triggering unit(RTU) configured to detect scattered radiation from pulses of theradiation beam.

A method of imaging Cherenkov light designated CB including the methoddesignated C where the timing signal synchronized to pulses of thepulsed radiation beam is provided by a source of the pulsed radiationbeam.

A method of imaging Cherenkov light designated CC including the methoddesignated C where the timing signal synchronized to pulses of thepulsed radiation beam is provided by logically “AND”-ing signals fromtwo radio-optical triggering units configured to detect scatteredradiation from pulses of the radiation beam.

A method of imaging Cherenkov light designated CD including the methoddesignated CC, CB, or CA wherein the PG-MPI camera is configured tointegrate the Cherenkov light over at least 10 pulses of the pulsedradiation beam while forming the Cherenkov light image.

A method of imaging Cherenkov light designated CE including the methoddesignated C, CA, CB, CC, or CD wherein the PG-MPI camera is used togenerate a background image of light received from tissue of the subjectwhen pulses of the radiation beam are not present; and furthercomprising subtracting the background image from the Cherenkov lightimage to form a corrected Cherenkov image.

A method of imaging Cherenkov light designated CF including the methoddesignated CE further comprising using calibration tables to convertcorrected Cherenkov light images to dose maps.

A method of imaging Cherenkov light designated CG including the methoddesignated CF further comprising using the dose maps to verify correcttreatment is being applied to a subject.

Changes may be made in the above methods and systems without departingfrom the scope hereof. It should thus be noted that the matter containedin the above description or shown in the accompanying drawings should beinterpreted as illustrative and not in a limiting sense. The followingclaims are intended to cover all generic and specific features describedherein, as well as all statements of the scope of the present method andsystem, which, as a matter of language, might be said to falltherebetween.

What is claimed is:
 1. A Cherenkov imaging system comprising: ahigh-speed radiation detector configured to provide a first timingsignal synchronized with pulses of radiation provided by a pulsedradiation beam source; the first timing signal is coupled to controloperation of at least one camera capable of imaging Cherenkov radiation;and a digital image-processing system; where the high-speed radiationdetector is selected from the group consisting of solid-state radiationdetectors and radiation detectors of the type comprising a scintillatorand a photodetector; where the at least one camera capable of imagingCherenkov radiation comprises a pulse-gated, multiple-pulse-integrating,(PG-MPI) CMOS image sensor synchronized through the first time signal topulses of the radiation beam source.
 2. A Cherenkov imaging system ofclaim 1 wherein a plurality of pixels of the PG-MPI CMOS image sensoreach comprise a photodiode coupled through a precharge gate to aprecharge level signal, the photodiode also coupled through a transfergate to a capacitor associated with a storage node, the storage nodealso coupled through a reset transistor to a reset voltage signal, thestorage node also coupled to a gate of a source follower, the source ofthe source follower being coupled through a select transistor to a datareadout line.
 3. The Cherenkov imaging system of claim 1 furthercomprising a second high-speed radiation detector configured to providea second timing signal, and the camera capable of imaging Cherenkovradiation is controlled to image Cherenkov radiation when both the firstand second high-speed radiation detectors simultaneously detectradiation.
 4. The Cherenkov imaging system of claim 3 wherein thedigital image-processing system is configured to use the camera capableof imaging Cherenkov radiation to capture an image of Cherenkovemissions and a background image, and to subtract the background imagefrom the image of Cherenkov emissions to generate a corrected Cherenkovimage.
 5. The Cherenkov imaging system of claim 4 wherein the digitalimage-processing system is further configured to apply calibrationtables to the corrected Cherenkov image to generate a dose map.
 6. Animaging unit comprising: a trigger input adapted for connection to abeam-on output signal provided by a pulsed radiation beam source, thetrigger input receiving a digital timing signal; apparatus configured tocommunicate the digital timing signal to trigger operation of at leastone camera capable of imaging Cherenkov radiation; where the cameracapable of imaging Cherenkov radiation is a pulse-gated,multiple-pulse-integrating, (PG-MPI) CMOS camera synchronized throughthe digital time signal to pulses of the radiation beam source.
 7. ACherenkov imaging system of claim 6 wherein each pixel of a plurality ofpixels of the PG-MPI CMOS camera comprises a photodiode coupled througha precharge gate to a precharge level signal, the photodiode alsocoupled through a transfer gate to a capacitor associated with thestorage node, the storage node also coupled through a reset transistorto a reset voltage signal, the storage node also coupled to a gate of asource follower, the source of the source follower being coupled througha select transistor to a data readout line.
 8. The Cherenkov imagingsystem of claim 6 wherein the digital image-processing system isconfigured to use the PG-MPI CMOS camera to capture an image ofCherenkov emissions and a background image, and to subtract thebackground image from the image of Cherenkov emissions to generate acorrected Cherenkov image.
 9. The Cherenkov imaging system of claim 8wherein the digital image-processing system is further configured toapply calibration tables to the corrected Cherenkov image to generate adose map.
 10. A method of imaging Cherenkov light emitted by a phantomor tissue comprising: providing a timing signal synchronized to pulsesof a pulsed radiation beam; applying the pulsed radiation beam to thephantom or tissue, the pulsed radiation beam causing the phantom ortissue to emit the Cherenkov light; imaging the Cherenkov light with apulse-gated, multiple-pulse-integrating, (PG-MPI) camera; imaging theCherenkov light being performed by integrating light received by thePG-MPI camera during multiple pulses of the radiation beam and notintegrating light received by the PG-MPI camera between pulses of theradiation beam.
 11. The method of claim 10 where the timing signalsynchronized to pulses of the pulsed radiation beam is provided by aradio-optical triggering unit (RTU) configured to detect scatteredradiation from pulses of the radiation beam.
 12. The method of claim 10where the timing signal synchronized to pulses of the pulsed radiationbeam is provided by a source of the pulsed radiation beam.
 13. Themethod of claim 10 where the timing signal synchronized to pulses of thepulsed radiation beam is provided by logically “AND”-ing signals fromtwo radio-optical triggering units configured to detect scatteredradiation from pulses of the radiation beam.
 14. The method of claim 10,11, 12 or 13 wherein the PG-MPI camera is configured to integrate theCherenkov light over at least 10 pulses of the pulsed radiation beamwhile forming the Cherenkov light image.
 15. The method of claim 14wherein the PG-MPI camera is used to generate a background image oflight received from tissue of the subject when pulses of the radiationbeam are not present; and further comprising subtracting the backgroundimage from the Cherenkov light image to form a corrected Cherenkovimage.
 16. The method of claim 15 further comprising using calibrationtables to convert corrected Cherenkov light images to dose maps.
 17. Themethod of claim 16 further comprising using the dose maps to verifycorrect treatment is being applied to a subject.
 18. The system of claim1 where the pulses of the radiation source have width on the order ofmicroseconds and repeat with period on the order of milliseconds.